Characteristics of Gastrointestinal Absorption of DX-9065a, a New Synthetic Anticoagulant

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著者

    • FUJII Yoshimine
    • Drug Metabolism & Physicochemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd.
    • TAKAHASHI Masayuki
    • Drug Metabolism & Physicochemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd.
    • MORITA Hiromi
    • Chemical Technology Research Laboratories, Daiichi Pharmaceutical Co., Ltd.
    • KIKUCHI Hiroshi
    • Drug Metabolism & Physicochemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd.
    • ARAMAKI Yukihiko
    • Faculty of Pharmaceutical Sciences, Tokyo University of Pharmacy and Life Science

抄録

  DX-9065a, a newly synthesized anticoagulant that selectively inhibits factor Xa, is a zwitterion and has characteristics of high water solubility and low lipophilicity. We predicted the fraction absorbed (Fa) of DX-9065a to be approximately 15-35% in humans, based on the boundary layer theory using the intestinal perfusion method in rats. However, human oral bioavailability was 2-3% in clinical trials, and the result of actual human bioavailability was lower than that of the predicted Fa. Thus, in this report, the reason for low oral bioavailability of DX-9065a was examined by <i>in vitro</i> and <i>in vivo</i> experiments. The factors affecting oral bioavailability of DX-9065a were not the hepatic first-pass effect, degradation of the drug in intestinal fluid, nor the interaction of the drug with the intestinal mucin. Furthermore, no effect of P-gp efflux was observed. Oral absorption of the drug in rats with bile duct ligation was significantly higher than that in normal rats with bioavailability of 17 and 3%, respectively. It was confirmed that bile acids inhibited DX-9065a absorption because DX-9065a interacted with bile acids to form insoluble complexes. The results suggest that the complex formation of DX-9065a with bile acids in the intestinal tract is an important factor affecting absorption of DX-9065a.<br>

収録刊行物

  • Drug metabolism and pharmacokinetics  

    Drug metabolism and pharmacokinetics 22(1), 26-32, 2007-02-28 

    The Japanese Society for the Study of Xenobiotics

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各種コード

  • NII論文ID(NAID)
    10018732905
  • NII書誌ID(NCID)
    AA1162652X
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    13474367
  • データ提供元
    CJP書誌  J-STAGE 
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